Table 2. Summary of primary efficacy outcomes in phase III RCTs with non-proportional hazards.
| Study | Outcome | Median follow-up | Protocol-defined expected median for the control group | Number of events out of total patients | Patterns of NPH | Log-rank (p value) | MaxCombo test (p value) | RMST* |
|---|---|---|---|---|---|---|---|---|
| Adjuvant therapy following surgery or ablation | ||||||||
| IMbrave050 - interim analysis 9 | RFS | 17.4 months | 20 months | Treatment arm (33%); active surveillance (40%) | Diminishing effects | 0.012 | 0.018 | 0.026 |
| IMbrave050 - second analysis 11 | RFS | 35.1 months | 20 months | 49% of patients in both arms | Diminishing effects | NR | 0.326 | 0.080 |
| TACE + IT | ||||||||
| LEAP-012 - interim analysis 5 | PFS | 25.6 months | 8 months | Treatment arm (56%); control arm (63%) | Diminishing effects | <0.001 | <0.001 | <0.001 |
| First-line systemic treatment | ||||||||
| HIMALAYA - STRIDE final analysis 29 | OS | 33.2 months | 10 months | Treatment arm (67%); control arm (75%) | Delayed effects | 0.003 | 0.002 | 0.001 |
| CheckMate 9DW - interim analysis 31 | OS | 35.2 months | 19 months | Treatment arm (58%) and control arm (68%) | Crossing of hazards | 0.018 | <0.001 | 0.030 |
The MaxCombo test and RMST were assessed. A p value <0.05 was considered statistically significant.
FU, follow-up; IT, immunotherapy; NPH, non-proportional hazards; NR, not reported; OS, overall survival; PFS, progression-free survival; RFS, recurrence-free survival; RMST, restricted mean survival time; STRIDE, durvalumab + tremelimumab; TACE, transarterial chemoembolization.
*
Assessed at the final time point at which more than 10% of patients remained at risk.